Summary: Francisella tularensis, the causative agent for tularemia, can infect humans by a number of routes, including vector-borne transmission. However, it is inhalation of the bacterium, and the resulting pneumonic tularemia, that represents the most dangerous form of disease. This is due to the short incubation time (3-5 days), non-specific symptoms, and a high mortality rate (greater than 80%) in untreated individuals. Furthermore, F. tularensis has been weaponized by both the United States and the former Soviet Union making it a viable candidate for use as a biological weapon. Despite over 80 years of research on F. tularensis around the world, very little is understood about the dynamic interaction of this bacterium with the host, especially following aerosol infection. In the last several years my laboratory has provided abundant evidence that one of the primary mechanisms by which F. tularensis successfully infects and replicates in the host is via active suppression of the host immune response in the lungs. We have a developed a reproducible murine model in which mice intranasally infected with 10 CFU to study the dynamic changes and progress of infection. This model has revealed several important points concerning pneumonic tularemia. One of the most important observations is that, unlike more attenuated strains, virulent F. tularensis actively suppresses the host immune response, including pulmonary dendritic cells, during the first few days of infection. Although we have not identified the primary mechanism of suppression there are several host molecules that appear to be involved, including Transforming Growth Factor-beta (TGF-beta) and Interferon-beta (IFN-beta). Furthermore, we have recently shown that CD14 is a critical player in the elicitation of inflammation following exposure of cells to F. tularensis. Cells that lack CD14 are still susceptible to infection, but fail to produce pro-inflammatory cytokines. We have also extended our initial observation that IFN-beta is a key regulatory cytokine in human cells to primary mouse alveolar macrophages. Similarly to human dendritic cells IFN-beta is the first cytokine induced following infection of alveolar macrophages in vitro and in vivo. The specific role and the mechanism in which F. tularensis and its components interacts induce IFN-beta in vivo and the role of this cytokine in mediating early suppression in the lung is currently being addressed in my laboratory.